Persistent Genital Arousal Disorder (PGAD) results in a spontaneous, persistent, and uncontrollable genital arousal, with or without orgasm or genital engorgement, unrelated to any feelings of sexual desire. It is a disabling condition caused by dysregulation of the dorsal sensory nerve, a distal branch of the pudendal nerve located bilateral to the vagina and clitoris. This condition has also been called Restless Genital Syndrome (RGS) and Persistent Sexual Arousal Syndrome (PSAS).
Physical arousal caused by this disorder can be very intense and persist for extended periods. Orgasm can provide temporary relief, but within hours the symptoms can return. Failure or refusal to relieve the symptoms often results in waves of spontaneous orgasms in women and ejaculation in men. The symptoms can be debilitating, preventing concentration on mundane tasks. Certain situations, such as riding in an automobile or train, or vibrations from mobile phones, can aggravate the condition, causing the discomfort to verge on pain. It is not uncommon for sufferers to lose some or all sense of pleasure over the course of time as release becomes associated with relief from pain rather than the experience of pleasure.
The cause or causes of PGAD are not yet known, though relief of symptoms has been noted from treatment with varenicline, as well as the use of antidepressants, antiandrogenic agents and anesthetizing gels. Psychotherapy with cognitive reframing of the arousal as a healthy response has also been used.
The genus Clostridium includes over one hundred and twenty seven species, grouped according to their morphology and functions. The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum toxin, which causes a neuroparalytic illness in humans and animals referred to as botulism. Seven generally immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C1, D, E, F and G, each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. For example, it has been determined that botulinum toxin type A is 500 times more potent, as measured by the rate of paralysis produced in the rat, than is botulinum toxin type B.
A commercially available botulinum toxin-containing pharmaceutical composition is sold under the trademark BOTOX® (available from Allergan, Inc., of Irvine, Calif.). BOTOX® consists of a purified botulinum toxin type A complex, albumin and sodium chloride packaged in sterile, vacuum-dried form. The botulinum toxin type A is made from a culture of the Hall strain of Clostridium botulinum grown in a medium containing N-Z amine and yeast extract.
A botulinum toxin has also been proposed for or has been used to treat skin wounds (U.S. Pat. No. 6,447,787), various autonomic nerve dysfunctions (U.S. Pat. No. 5,766,605), tension headache, (U.S. Pat. No. 6,458,365), migraine headache pain (U.S. Pat. No. 5,714,468), post-operative pain and visceral pain (U.S. Pat. No. 6,464,986), hair growth and hair retention (U.S. Pat. No. 6,299,893), psoriasis and dermatitis (U.S. Pat. No. 5,670,484), injured muscles (U.S. Pat. No. 6,423,319) various cancers (U.S. Pat. No. 6,139,845), smooth muscle disorders (U.S. Pat. No. 5,437,291), nerve entrapment syndromes (U.S. Published Patent Application 20030224019, filed Feb. 27, 2003), acne (WO 03/011333) and neurogenic inflammation (U.S. Pat. No. 6,063,768). Controlled release toxin implants are known (see e.g. U.S. Pat. Nos. 6,306,423 and 6,312,708) as is transdermal botulinum toxin administration (U.S. Published Patent Application No. 20040009180, filed Jul. 11, 2002), all herein incorporated entirely by reference.
An approach currently being exploited to expand Clostridial toxin-based therapies involves modifying a Clostridial toxin such that the modified toxin has an altered cell targeting capability for a neuronal or non-neuronal cell of interest. Called re-targeted endopeptidases or Targeted Vesicular Exocytosis Modulator Proteins (TVEMPs), these molecules achieve their exocytosis inhibitory effects by targeting a receptor present on the neuronal or non-neuronal target cell of interest. This re-targeted capability is achieved by replacing the naturally-occurring binding domain of a Clostridial toxin with a targeting domain (or targeting moiety) showing a selective binding activity for a non-Clostridial toxin receptor present in a cell of interest. Such modifications to the binding domain result in a molecule that is able to selectively bind to a non-Clostridial toxin receptor present on the target cell. A re-targeted endopeptidase can bind to a target receptor, translocate into the cytoplasm, and exert its proteolytic effect on the SNARE complex of the neuronal or non-neuronal target cell of interest.
An important difference between re-targeted endopeptidases such as TVEMPs and native Clostridial toxins is that because the TVEMPs do not target motor neurons, the lethality associated with over-dosing a mammal with a TVEMP is greatly minimized, if not avoided altogether. For example, opioid TVEMPs can be administered at 10,000 times the therapeutically effective dose before evidence of lethality is observed, and this lethality is due to the passive diffusion of the molecule and not via the intoxication process. Thus, for all practical purposes TVEMPs are non-lethal molecules. Additional disclosure relating to TVEMPs can be found in U.S. application Ser. No.'s 12/303,078 and 12/868,510, both incorporated entirely by reference.